Inclusion: IHS migraine criteria; migraine frequency of 3 or more per month, 1 month or more since discontinuation of any previous migraine prophylaxis; adequate contraceptionExclusion: secondary, daily, and analgesic abuse headaches were adequately excluded. Other exclusions: lactation; other severe medical illness, history of alcohol or drug abuse, previous treatment with gabapentin, contraindications to gabapentin

The SES included all randomised patients: 89; all had migraine without aura; 21/89 also had migraine with aura; 68 were females and 21 males; mean age in gabapentin group 42 (range 20 to 68); mean age in placebo group 42 (range 23 to 68). 46 allocated to receive gabapentin and 43 allocated to receive placebo. The efficacy evaluable population comprised 53 participants. Among them, the proportion with migraine with aura is not reported; 42 were females and 11 males; mean age in gabapentin group 43 (range 20 to 68); mean age in placebo group 40 (range 24 to 59). 22 allocated to gabapentin and 31 to placebo

Interventions

Gabapentin 900 mg/day versus placebo (12 weeks). No information on titration. Capsules of gabapentin (300 mg) or placebo were given 3 times a day

Outcomes

Migraine attack frequency calculated on a 28-day basis. Response ratio defined as difference in attack frequency from baseline to treatment period divided by the sum of attacks during baseline and treatment. Subjective evaluation of improvement of migraine. Duration of attacks (hours) under treatment and the percent reduction in duration relative to baseline. Average pain. Maximal pain during attacks. Change in patients with aura symptoms. The relation between response ratio and dose per kilogram body weight. AEs

Time point(s) considered in the review: entire 12-week treatment phase

Notes

Since the baseline was retrospective, change scores from baseline were excluded from the analyses of the present review. This report reveals essential limitations in design and conduct of the study. There are differences between the original protocol (appendix) and the study protocol that is discussed in the main body of the report. Initially it was intended that dropouts (eg, for lack of efficacy) would be replaced with newly randomised subjects, but this does not appear in the final description. Also, all centres were initially to include migraineurs with at least 8 attacks per month, but it is clear that sometime during the conduct of the study this criterion was relaxed to at least 2 attacks per month for most centres. This implies that the design may have changed during the execution of the study. This may have influenced outcomes

Funders of the trial: Goedecke AG – Research and Development, Freiburg

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Randomisation per centre in permuted blocks of 10. No information found on method used for sequence generation

Allocation concealment (selection bias)

Unclear risk

No information

Blinding of participants and personnel (performance bias) All outcomes

High risk

Both participants and clinicians were blinded. Medications were given as identical capsules distributed in bottles. Bottle labels contained medication number only. It is not specified how subject number was linked to medication number on bottle. Given that the number of gabapentin subjects erroneously receiving other prophylaxis was nearly 3 times higher in the gabapentin group than in the placebo group, it is likely that the blinding was inadequate

Blinding of outcome assessment (detection bias) All outcomes

Unclear risk

No information

Incomplete outcome data (attrition bias) All outcomes

High risk

High number of protocol violators due to the initiation or continuation of other prophylactics (19 of those allocated to gabapentin; 7 of those allocated to placebo). It is not clear whether the majority initiated other prophylaxis prior to or after randomisation, the higher efficacy means in the gabapentin ITT population (with violators) compared to efficacy population (without violators) suggest that a significant number may have been initiated after randomisation, possibly because of lack of efficacy. Only the data for the smaller efficacy population are included in this review

Selective reporting (reporting bias)

Unclear risk

The research report was never published and results would have remained unobtainable had it not been for the discovery process in a legal case. The response ratio measure was not mentioned in the original protocol (appendix A.2)

Rule for use of acute medication: not explicitly reported, but see notes

Methodological quality score: 5

Participants

Inclusion: IHS migraine criteria; migraine frequency of 3 to 8 attacks per month for the previous 3 months; no more than 2 previous migraine prophylactic medications. Mixed headaches were included if tension-type headache attacks occurred on 10 or fewer days per month; subgroups cannot be distinguished

Time point(s) considered in the review: last (third) month of treatment phase

Notes

Ergotamine use up to 2 days per week permitted. NSAIDs, analgesics, benzodiazepines, cyproheptadine, baclofen, SSRIs up to 3 days per week permitted. mITT does not conform to recent recommendationsFunders of the trial: Warner-Lambert Company, New Jersey

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer-generated randomisation schedule, 2:1 ratio

Allocation concealment (selection bias)

Low risk

Each investigator was provided with "blinded" medication

Blinding of participants and personnel (performance bias) All outcomes

Low risk

Placebo capsules matched active treatment. During the double-blind phase, investigators, patients, study monitors, and observers were blinded to codes until after the clinical database was locked

Blinding of outcome assessment (detection bias) All outcomes

Unclear risk

No information

Incomplete outcome data (attrition bias) All outcomes

Low risk

No concerns over incomplete outcome data

Selective reporting (reporting bias)

Unclear risk

The research report was never published and results would have remained unobtainable had it not been for the discovery process in a legal case

Prospective, randomised, double-blind, parallel-group trial. The 16-week study consisted of a 4-week, single-blind baseline period and a 12-week, double-blind treatment period (divided into a 4-week titration period and an 8-week stable dosing period (the first 4 weeks called Stabilization Period 1 and the second 4 weeks called Stabilization Period 2))

Discontinuation rate: gabapentin 25%, placebo 24%

Compliance (adherence) data: compliance was to be measured by counting unused medication and confirming lack of gabapentin in blood drawn from placebo group, but results not summarised in the research report

Rule for use of acute medication: symptomatic medications (eg, aspirin, acetaminophen, NSAIDs, tramadol, codeine and codeine derivatives, dihydroergotamine, and ergotamine (< 10 mg/week or ≤ 5 mg/day), sumatriptan, Midrin, antiemetics) were permitted on an "as needed" basis for treatment of individual headaches and were to have been taken 1 hour following initial onset of an attack. These medications were to have been taken for less than 3 days each week on average. Narcotics were not to have been used as a first-line treatment

Methodological quality score: 4

Participants

Inclusion: migraine with or without aura according to IHS criteria; migraine frequency 3 to 8 episodes per month for each of the 3 months prior to screening and during the 4-week baseline period; history of migraine at least 6 months prior to screening. Ages 16 to 75. Other inclusion criteria: capability of compliance and ability to understand and follow the instructions of the investigator; understanding and capability of completing the study diaries as described in the protocol; informed consent obtained from the patient or legal guardian

Exclusion: chronic daily headache or TTH occurring > 10 days/month, medication overuse headache and other secondary headaches were adequately excluded. Other exclusions: if sexually active, female patients must have been practicing a reliable method of contraception and must have had a negative serum pregnancy test; female patients who were using oral contraceptives were to have been using the same product for at least 3 months prior to study entry; previously untreated for migraine prophylaxis or having failed an adequate trial (eg, at least 1 month of treatment at a full therapeutic dose) on no more than 2 prophylactic anti-migraine medications; pregnant or nursing; having received prophylactic anti-migraine medication for a period equal to or greater than 5 half-lives of that medication before entering the baseline phase; previous treatment with gabapentin; migraine aura without headache only; serious neurological, psychiatric, or other medical disorder

Setting: 11 centres

Country: USA

Among the 157 randomised patients (gabapentin 102; placebo 55), 150 received study medication and comprise the SES. Of the SES, 57 had migraine with aura and 93 migraine without aura; 123 were females and 27 males; mean age 39.1 ± 11.0; age range 16 to 64. 95 received gabapentin and 55 received placebo. mITT analysis of 122 patients: 48 had migraine with aura; 97 were females and 25 males; mean age 39.2 ± 11.0 (range 16 to 64). 76 received gabapentin and 45 received placebo

Interventions

Gabapentin 1800 mg/day versus placebo (12 weeks). Gabapentin 300 mg capsule starting with 1 at night-time and then titrated up to 1800 mg/day divided into BID dosing during a 4-week period. Thereafter stable dosing. 94/95 SES patients treated with active treatment received 1800 mg/day as the final stable dose. Placebo capsules were titrated in the same manner as active treatment

Outcomes

Headache frequency per 28 days. Proportion of responders (≥ 50% reduction in migraine attacks). Average severity at peak intensity. Average duration of migraine headache. Average functional ability at the time of peak intensity. Aura severity. Number of days per 4 weeks with a migraine headache. SF-36 quality of life. AEs. Vital signs. Physical examinations. Laboratory assessments

Time point(s) considered in the review: Stabilization Period 2, ie, third month of treatment

Notes

Funders of the trial: Warner-Lambert Company, New Jersey

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Randomisation in a 2:1 ratio was performed by the Clinical Pharmaceutical Operations (CPO) Department of Parke-Davis. No information on method used for randomisation found

Allocation concealment (selection bias)

Low risk

Blinded medication provided by CPO or other designated facility based on the randomisation code

Blinding of participants and personnel (performance bias) All outcomes

Low risk

Clinicians and patients were blinded. Gabapentin and placebo were provided as capsules identical in size and colour by Parke-Davis, packaged in patient-specific bottles and shipped to investigators

Blinding of outcome assessment (detection bias) All outcomes

Unclear risk

No information

Incomplete outcome data (attrition bias) All outcomes

Low risk

No concerns over incomplete outcome data

Selective reporting (reporting bias)

Unclear risk

The research report was never published and results would have remained unobtainable had it not been for the discovery process in a legal case

Rule for use of acute medication: use of acute migraine medication was permitted for breakthrough migraine attacks Methodological quality score: 4

Participants

Inclusion: migraine with or without aura according to ICHD-II; migraine frequency ≥ 3 attacks and ≥ 4 calendar days per month during each of the 3 months prior to screening and during baseline; migraines consistent in incidence and severity over time; history of migraine at least 1 year prior to screening; onset of migraine before age 50. Ages 18 and above. Other inclusion criteria: written informed consent

Blinding of participants and personnel (performance bias) All outcomes

Unclear risk

It is assumed from the term 'double-blind' that participants and clinicians were blinded. No information on method used. Potential unblinding by AEs (notably dizziness)

Blinding of outcome assessment (detection bias) All outcomes

Unclear risk

No information

Incomplete outcome data (attrition bias) All outcomes

High risk

Subjects have been randomised despite missing baseline values. Missing values in secondary outcomes not accounted for

Selective reporting (reporting bias)

High risk

Within-group changes (with standard deviations) from baseline in mean migraine frequencies during the double-blind period lacking. Only differences in changes (with 95% CIs) from placebo given in publication. Supplementary information requested corresponding author, but no reply

Post hoc subgroup analysis of RR 995-00074 (included). "Modified intention-to-treat" (mITT) population described in Mathew 2001 (n = 87; gabapentin 56, placebo 31) is smaller and more select than the mITT population described in RR 995-00074 (n = 113; gabapentin 77, placebo 36). This is due to the exclusion in Mathew 2001 of participants who did not maintain a stable dose of 2400 mg/day of study medication during the last (third) month of the treatment phase. By focusing on this narrower population, Mathew 2001 overstates the efficacy of gabapentin when compared with the results as reported in RR 995-00074 (McCrory 2008; Saris 2010; Vedula 2009)

Extended abstract only; insufficient information provided. Close similarities in the design of the trial and the fact that there are several names in common between the authors of this abstract and the outside investigators listed in RR 4301-00066 lead us to conclude that this abstract reports an interim analysis of RR 4301-00066 (included). Some differences between this abstract and RR 4301-00066 in the results and numbers of patients are likely explained by this abstract being an interim report (before completion) while RR 4301-00066 represents a final report (after completion)